Abstract
Despite clinical evidence indicating a close relationship between olfactory dysfunction and Alzheimer’s disease (AD), further investigations are warranted to determine the diagnostic potential of nasal surrogate biomarkers for AD. In this study, we first identified soluble amyloid-β (Aβ), the key biomarker of AD, in patient nasal discharge using proteomic analysis. Then, we profiled the significant differences in Aβ oligomers level between patient groups with mild or moderate cognitive decline (n = 39) and an age-matched normal control group (n = 21) by immunoblot analysis and comparing the levels of Aβ by a self-standard method with interdigitated microelectrode sensor systems. All subjects received the Mini-Mental State Examination (MMSE), Clinical Dementia Rating (CDR), and the Global Deterioration Scale (GDS) for grouping. We observed higher levels of Aβ oligomers in probable AD subjects with lower MMSE, higher CDR, and higher GDS compared to the normal control group. Moreover, mild and moderate subject groups could be distinguished based on the increased composition of two oligomers, 12-mer Aβ*56 and 15-mer AβO, respectively. The longitudinal cohort study confirmed that the cognitive decline of mild AD patients with high nasal discharge Aβ*56 levels advanced to the moderate stage within three years. Our clinical evidence strongly supports the view that the presence of oligomeric Aβ proteins in nasal discharge is a potential surrogate biomarker of AD and an indicator of cognitive decline progression.
Highlights
Abbreviations AD Alzheimer’s disease Clinical Dementia Rating (CDR) Clinical dementia rating Aβ Amyloid-β Aβ42 Amyloid-β 1–42 peptide CSF Cerebrospinal fluid ELISA Enzyme-linked immunosorbent assay Global Deterioration Scale (GDS) Global deterioration scale HRP Horseradish peroxidase MDS Multimer detection system Mini-Mental State Examination (MMSE) Mini mental state examination MRI Magnetic resonance imaging
We demonstrated that Aβ was expressed in the nasal discharge from AD patients by liquid chromatography-mass spectrometry (LC–MS) and that changes in the oligomeric Aβ composition in the nasal discharge were correlated with cognitive decline among the patient groups by immunoblot analysis
Significant differences between the groups were detected in the Mini-Mental State Examination (MMSE) and the Clinical Dementia Rating (CDR) scores (Table 1)
Summary
Abbreviations AD Alzheimer’s disease CDR Clinical dementia rating Aβ Amyloid-β Aβ42 Amyloid-β 1–42 peptide CSF Cerebrospinal fluid ELISA Enzyme-linked immunosorbent assay GDS Global deterioration scale HRP Horseradish peroxidase MDS Multimer detection system MMSE Mini mental state examination MRI Magnetic resonance imaging. The high prevalence of olfactory dysfunction among AD patients indicates a possible correlation between olfactory deficits and AD pathogenesis (i.e., the expression of Aβ in the olfactory tissue)[13,14,15,16] Based on this clinical and experimental evidence, we hypothesized that nasal discharge could be a candidate to monitor pathophysiological changes in the olfactory system during neurodegeneration that may result in AD. Our previous animal study supports the hypothesis by reporting that specific oligomeric Aβ (Aβ*56 and AβO) was existed in the olfactory epithelium at different progression stages of AD with evident cognitive impairment in AD transgenic mice; Tg2576, a Swedish mutant form of human amyloid precursor protein (APP) (KM670/671NL) (promoter: hamster prion protein (PrP))[16]. We assessed alterations in two specific types of oligomeric Aβ levels in nasal discharges in three-year longitudinal cohorts
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